Patent literature 1 discloses novel amide derivatives useful in preventing and treating diseases in which herpesviruses are involved. In particular, the compound described in Example 27 (hereinafter referred to as compound A) and the compound described in Example 2 (hereinafter referred to as compound B) are considered to be useful. It is expected that the daily dose is generally approximately 0.001 to 50 mg/kg, preferably 0.01 to 30 mg/kg, more preferably 0.05 to 10 mg/kg, for oral administration, and that the daily dose is administered once or divided into multiple doses per day. The dose is appropriately determined depending on each case, in accordance with symptoms, age, sex, and the like.
Because these amide derivatives per se, including compounds A and B, are slightly soluble, it is necessary to improve the solubility and absorption. In addition, it is expected that the dose is approximately 0.001 to 50 mg/kg, and therefore, for large doses, it is necessary to reduce the size of the formulation. Further, a solid dispersion having properties suitable for formulation, for example, a specific volume, compression moldability, or the like, and having an excellent stability is needed.
From the results of toxicity tests, the specification of analogous substances contained in a drug product is, for example, 2% by weight or less, and 0.6% by weight or less in another embodiment, with respect to the amount of the drug substance. Non-patent literature 1 published by the Japanese Ministry of Health, Labor and Welfare in June, 2003 includes a description about the specification of drug products, namely the concept of degradation products (impurities) in drug products as observed at stability tests. According to the description, when the amount of the drug substance to be administered per day is 10 mg or more to less than 2 g, the threshold of a degradation product requiring safety qualification in a drug product is a lower one of either 0.2% as the percentage of the degradation product contained in a drug substance or 2 mg as the total daily intake of the degradation product. Therefore, when the drug product contains, for example, 200 mg of the drug substance, the specification of a degradation product which can be generally determined without any safety qualification of the degradation product is preferably 0.2% or less as the percentage of the degradation product contained in a drug substance. The drug product will be put on the market based on the results of clinical trials.
Formulations containing compound A (N-(2,6-Dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) are 50 mg tables, 100 mg tablets, and 200 mg tablets. To ensure the stability of these formulations, the ratio of the main degradation product (hereinafter referred to as F1) of compound A (N-(2,6-Dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) with respect to the sum of compound A (N-(2,6-Dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) and degradation products thereof should be, for example, 2% by weight or less, 0.6% by weight or less in another embodiment, 0.2% by weight or less in still another embodiment.
As a method for solubilizing a slightly soluble drug, patent literature 2 discloses a solid composition containing an extremely hardly water soluble drug in the form of an amorphous substance, a polymer base, and a nonionic surfactant, to solve problems as observed in conventional solid dispersion, that is, to improve the decreased dissolution rate of a solid dispersion, or a decreased solubility caused by drug precipitation after a certain period of time.
However, patent literature 2 does not refer to the compound of the formula (I), and further improvements are necessary to prepare a pharmaceutical composition.